The invention relates to cationic antimicrobial polymers for antimicrobial applications and delivery of bioactive materials, and more specifically to unimolecular cationic polycarbonates and/or polyestercarbonates for antimicrobial applications, gene delivery, and/or drug delivery.
Most conventional antibiotics (e.g., ciprofloxacin, doxycycline and ceftazidime) do not physically damage the cell wall but rather penetrate into the target microorganism and act specifically on targets such as double-stranded DNA breakage, inhibition of DNA gyrase, blockage of mitotic factors or the triggering of intrinsic autolysins. As a consequence, the bacterial morphology is preserved and the bacteria can readily develop resistance. In contrast, most cationic peptides (e.g., magainins, cecropins, protegrins and defensins) do not have a specific target in microbes, and interact with the microbial membranes through electrostatic interactions, thereby inducing terminal damage to microbial membranes.
It has been shown that macromolecular cationic antimicrobial peptides can overcome bacterial resistance. Most antimicrobial peptides possess cationic and amphiphilic features. Although efforts have been made to design antimicrobial peptides with various structures over the last two decades, clinical success has been limited. To date, only four cationic peptides have successfully entered Phase III clinical trials for wound healing. This is mainly due to cytotoxicity caused by the cationic nature of peptides (e.g., hemolysis), in vivo short half-life (labile to proteases), and high manufacturing cost.
Amphiphilic biodegradable cationic block copolycarbonates comprising hydrophilic cationic blocks and hydrophobic blocks are also limited in their use as antimicrobials. The block copolycarbonate molecules aggregate in water to form cationic micelles. Although the cationic micelles are active against Gram-positive bacteria (e.g., Bacillus subtilus), they are less active or non-effective against Gram-negative bacteria (e.g., Escherichia coli). The micelles also de-aggregate at infinite dilution, which lowers their toxicity to bacteria. Thus, the critical micelle concentration (CMC) observed with linear block copolycarbonates is currently too high for effective systemic administration of these materials.
Gene therapy holds promise for the treatment of various hereditary and acquired diseases that arise from genetic aberrations. Effective gene therapy requires three separate events. First, the genetic material which is intended to be delivered must be effectively condensed into a particle having an appropriate size to facilitate extended circulation half life. Secondly, the condensed particle must provide protection from the host organism's natural defense mechanisms, which are designed to eliminate any foreign genetic material. Finally, the nucleic acids must be unpackaged at a desired location allowing their delivery and ultimately transcription.
A continuing challenge exists in gene therapy to develop a safe and efficacious vector that can package and protect the genetic material in extracellular environments and penetrate the cell to readily release its genetic cargoes. While viral vectors have superior transduction capabilities, their extensive clinical applications have been greatly limited by significant immunogenic and carcinogenic risks, costly production, and size restrictions on the encapsulated gene. Of the various synthetic transporter materials available, poly(ethylenimine) (PEI) represents a standard for in vitro gene transfection efficiencies. However, the clinical potential of PEI has been drastically limited due to its non-biodegradability and high cytotoxicity.
Other gene delivery materials, including poly(β-amino esters) (PBAEs), modified PEIs and dendrimers based on poly(amidoamine) (PAMAM) and poly(L-lysine), are not without unresolved synthetic issues such as relatively large polydispersities, complex molecular architectures requiring multiple production steps, and high cost of starting materials (in the case of amino acids). A narrow molecular weight system is believed to be crucial in the clinical settings as individual molecular weight fractions of a polydisperse system are expected to exhibit distinct pharmacological activities in vivo.
Currently, a growing and urgent need exists for enzymatically biodegradable, non-cytotoxic antimicrobial materials that i) exhibit higher toxicity toward a combination of Gram-negative and Gram-positive microbes, and ii) disperse in aqueous solution as unimolecular nanostructures having an average particle diameter of 10 nm to 300 nm. This size range is generally suitable for cell wall penetration, and potentially expands the utility and value of the antimicrobial materials as multi-use delivery vehicles for genes and/or drugs.